Download Restrict IV acetylcysteine use for the prevention of radiocontrast

Volume 25, Number 9
October 2011 Drugs & Therapy
B
U
◆
◆
L
FORMULARY UPDATE
The Pharmacy and Therapeutics Committee met September 20,
2011. 7 products were added in the
Formulary, and 2 were deleted and
designated nonformulary and not
available. 3 criteria for uses were
approved including 2 restrictions.
◆ADDED
Asenapine (Saphris®)*
*Restricted: continuation from home
& Psychiatry Service
Belatacept (Nulojix®)*
*Restricted to renal transplant patients
Menthol Lozenges (Generic)
Prothrombin Complex
Concentrate (Profilnine® SD)
*Restricted: life-threatening
hemorrhage due to warfarin overdose
Rilpivirine (Edurant®)
Rilpivirine-EmtricitabineTenofovir (Complera®)
Rivaroxaban (Xarelto®)
◆ DELETED
◆
L
◆
E
◆
†Nonformulary and not available
◆CRITERIA-FOR-USE CHANGES
Brentuximab Vedotin (Adcetris®)*
*Added in the Chemotherapy Policy
Cytomegalovirus Immune
Globulin (Cytogam®)‡
‡Off-label Use in Pregnant Women
Endorsed
Vemurafenib (Zelboraf®)*
*Added in the Chemotherapy Policy
(continued on next page)
◆
I
◆
N
PROPOSAL
Restrict IV acetylcysteine use for
the prevention of radiocontrastinduced nephropathy
T
he P&T Committee will be considering a proposal to limit the use
of intravenous (IV) n-acetylcysteine
(NAC) for the prevention of radiocontrast-induced nephropathy (RCIN).
Attending physicians who would like
to comment on these proposed restrictions should email their comments to
[email protected] by October 25, 2011.
There will be an effort to let the major
users of IV NAC know about this
proposed change, but notification in
the newsletter is intended to make this
proposal known to all current users of
this product. Last year, approximately a
half a million dollars was spent on this
dosage form.
◆
Attending physicians who
would like to comment on
these proposed restrictions
should email their
comments by October 25.
Cepacol® Lozenges†
Telavancin (Vibativ®)†
T
The current proposal is to limit the
use of IV NAC to a single dose unless the patient meets specific criteria
regarding the volume of contrast dye
used AND the existence of pre-existing
renal dysfunction. Data suggest that
only very large dye loads (ie, greater
than 200 mL) place the patient at risk.
For example, patients receiving routine
CT scans with dye should NOT receive
IV NAC. Patients with pre-existing renal dysfunction are defined by an estimated glomerular filtration rate (eGFR)
less than 30 mL per minute or both an
eGFR less than 50 mL per minute and
either diabetes or congestive heart failure. The Division of Nephrology of the
Department of Medicine agrees with
this proposal.
RCIN is a potentially serious adverse
drug reaction that occurs in up to 50%
of high-risk patients requiring contrast for coronary angiography and
computed tomography. NAC is often
given to prevent the development of
RCIN despite mixed results from
clinical trials.
Eleven randomized controlled trials
have compared IV NAC to hydration
for the prevention of RCIN. There are
no studies comparing IV and oral NAC.
Trials investigating IV NAC have produced conflicting results. The trials are
heterogeneous regarding IV NAC dosing regimens, hydration regimens, volumes of contrast used, and RCIN risk
level. For example, the rate of RCIN in
control groups ranged from 0% to 33%.
Only 3 out of the 11 trials demonstrated
a benefit in preventing RCIN. Some trials have a higher incidence of RCIN in
the IV NAC arm, further confusing the
issue. The trials suggesting possible
efficacy for IV NAC help determine
which patients are good candidates
versus those that are not.
IV NAC may be beneficial when
administered to patients at high risk
for RCIN that receive high volumes
of contrast dye. Oral NAC should be
given in most cases, if NAC use is
deemed necessary. Given the option
between therapies with equally poor
evidence, it is reasonable to choose the
most economical alternative. IV NAC is
roughly 10 times more expensive than
oral NAC.
If the P&T Committee approves the
restriction of IV NAC, patients not
meeting the dye volume and eGFR
requirements would be switched to
oral NAC or NAC would be discontinued after the first dose.
◆
INSIDE THIS ISSUE
◆ Breaking news on bisphosphonates
2
Formulary update, from page 1
Asenapine is a sublingual secondgeneration antipsychotic with a
labeled indication for acute and
maintenance treatment of schizophrenia, as well as monotherapy and
adjunctive therapy of manic or mixed
episodes for bipolar mania. Asenapine has high affinity and antagonistic action at serotonin, dopamine,
alpha-adrenergic, and histamine
receptors with no appreciable activity
at muscarinic cholinergic receptors.
Some hypothesize this activity allows
better control of negative symptoms
of schizophrenia and decreased anticholinergic adverse effects; however,
whether these differences translate
to clinically important effects compared with other agents is unproven.
Efficacy in schizophrenia is inconsistent. Attrition among asenapine
patients has been more than with
comparators due to adverse events
and lack of efficacy. No dose-response
effect has been shown with flexible
dosing regimens. Asenapine has
not shown better negative symptom
control in the acute and maintenance
treatment of schizophrenia. In the
treatment of bipolar mania, asenapine was not consistently better than
placebo in response and remission
rates.
No currently available study has
been designed to compare asenapine
to another active treatment. Exclusion of patients with common comorbid conditions (eg, substance abuse,
rapid cycling) limits external validity
for general psychiatry patients. Food
and liquid intake restrictions, as well
as twice-daily dosing, may impose
additional barriers to compliance in
an already noncompliant population.
Low bioavailability when swallowed
is an obstacle to therapeutic efficacy.
Based on current evidence, asenapine does not appear to provide an
advantage over other antipsychotics.
A similar agent listed in the Formulary, olanzapine orally disintegrating
tablets (Zyprexa® Zydis®), consistently outperformed asenapine in indirect
comparisons for schizophrenia maintenance and acute bipolar treatment.
Asenapine was added in the
Formulary but restricted to patients
who fail treatment with other atypical antipsychotics. The Psychiatric
Service is required for initiation of
therapy. Patients admitted already
on asenapine may continue therapy.
Asenapine cannot be used for agitation in general medicine patients or
critically ill patients.
Belatacept is a potent antagonist
of CD80 and CD86 ligands present
on antigen-presenting cells, which
are responsible for CD28 activation.
Produced by CD28, the co-stimulation
pathway of T-cell activation and proliferation is essential to the immune system’s ability to identify a transplanted
organ as foreign.
After phase II trials revealed that
belatacept may provide adequate immunosuppression compared to calcineurin inhibitors (eg, cyclosporine or
tacrolimus) while avoiding some of
the chronic toxicities associated with
calcineurin inhibitors, larger phase III
studies were performed. The Belatacept Evaluation of Nephroprotection
and Efficacy as First-Line Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection
and Efficacy as First-Line Immunosuppression Trial-EXTended criteria
donors (BENEFIT-EXT) were some of
the largest studies ever performed in
kidney transplant recipients. In both
standard criteria and extended criteria
kidney donors, belatacept was associated with similar patient/graft survival
when compared to the calcineurin inhibitor cyclosporine. Belatacept-treated
patients had better renal function and
more favorable cardiovascular profiles
compared to cyclosporine. However,
belatacept was associated with an
increased incidence of acute rejection
and cases of post-transplant lymphoproliferative disorder (PTLD), a rare and
serious adverse event occurring after
transplantation. PTLD occurred most
often in patients who were EpsteinBarr Virus seronegative.
Because the cost of each vial of
belatacept is high (approximately $700)
and each transplanted patient will receive approximately 6 vials during their
hospital stay, the use of belatacept will
add considerably to pharmaceutical
expenditures.
Whether improvements in renal function and cardiovascular markers will
result in improved long-term outcomes
and the safety data on this new drug
class remains largely unknown. There
are concerns about rare but serious
adverse effects (PTLD and progressive multifocal leukoencephalopathy).
Therefore, belatacept was added in the
Formulary and restricted to use in renal
transplant recipients. After a year, the
impact of this agent on reimbursements
for renal transplantation and utilization
data will be reviewed by the P&T Committee.
Menthol is a common ingredient
in oral throat lozenges. Until recently,
Cepacol® Lozenges were listed in the
Formulary. Cepacol® Lozenges were
deleted from the Formulary and designated nonformulary and not available
after they were reformulated to contain
benzocaine. A plain menthol-containing
lozenge will now be listed in the Formulary.
In March 2010, benzocaine-containing
lozenges (Chloraseptic® Lozenges) and
spray (Hurricaine® Spray) were deleted
from the Formulary and designated
nonformulary and not available. These
decisions were made to decrease the
risk of methemoglobinemia that has
been associated with the mucosal use
of benzocaine.
A menthol-containing lozenge, like
Cepacol®, that did not contain benzocaine was offered as an alternative to
Chloraseptic® Lozenges. Chloraseptic®
Spray, which uses phenol as an active
ingredient, is another alternative to
benzocaine-containing lozenges.
Hall’s Sugar-Free Triple-SoothingAction lozenges were selected because they contained a similar amount
of menthol (5 mg) per lozenge and are
sugar-free [but do not contain sorbitol,
which can cause diarrhea].
Profilnine® SD is a 3-factor prothrombin complex concentrate (PCC)
containing primarily factors II, IX, and
X. PCC is also known as Factor IX
Complex, but it will be listed in EPIC
as prothrombin complex concentrate in
an attempt to prevent confusion with
other factors (eg, recombinant Factor
IX). Despite its labeled indication for
the prevention and control of bleeding
in patients with Factor IX deficiency
due to hemophilia B, it is used primarily for the management of serious
bleeding associated with excessive
anticoagulation with warfarin.
When a 3-factor PCC is used to treat
excessive anticoagulation, fresh frozen
plasma (FFP) is usually given at the
same time to supplement the amount
of Factor VII (FVII). For life-threatening bleeding, guidelines from the
American College of Chest Physicians
(ACCP) recommend holding warfarin
therapy and administering FFP, PCC,
or recombinant FVIIa (NovoSeven® RT)
along with 10 mg IV vitamin K, repeating if needed, depending on the INR.
The available evidence for the use
of PCC for the treatment of excessive
warfarin anticoagulation is limited.
The ideal evidence for the use of Profilnine® SD for the treatment of warfarin toxicity would be randomized controlled trials assessing the safety and
efficacy of products (ie, PCC vs FVIIa).
Unfortunately, no such evidence exists for the available PCC products or
FVIIa. One recently completed, but
unpublished, non-randomized trial
used a parallel design to compare
FVIIa, PCC, and FFP in intracranial
hemorrhage with the primary outcome of INR normalization as defined
by an INR less than 1.4. If this study
is published, it may provide additional
evidence. The evidence for products
currently on the market mostly comes
from observational studies and case
series. Recent evidence suggests that
FVIIa can correct elevated INR, but
(continued on next page)
Formulary update, from page 2
may not decrease bleeding time or
blood loss.
Viral (hepatitis A, B, C, HIV, HTLV1, and parvovirus B19) transmission
is possible with PCCs as they are derived from human plasma. Since FFP
is used with 3-factor PCC, the risks
associated with transfusion-related
acute lung injury must be considered.
It is characterized by acute onset of
noncardiogenic pulmonary edema
and occurs in about 1 of every 5000
transfusions; it is the leading cause of
transfusion-related deaths in the US
(~50%).
The use of PCC plus FFP is similar
in cost to FVIIa. The doses of FVIIa
and Profilnine SD® can greatly vary
between patients. While treating a
patient with PCC and FFP appears to
be less expensive than FVII alone, if
a patient needs a higher PCC dose or
more units of FFP, it can be more costly. In addition, miscellaneous costs
(extra personnel, etc.) in handling the
additional administration of FFP may
be an issue.
Profilnine® SD was added in the
Formulary for use in life-threatening
hemorrhages due to warfarin overdose. Each use will be reviewed
immediately after it is administered to
assure appropriate use.
Rilpivirine is a novel human immunodeficiency virus type-1 (HIV-1)
non-nucleotide reverse transcriptase
inhibitor (NNRTI). Rilpivirine has a
labeled indication for the treatment of
HIV-1 in treatment-naïve patients.
Rilpivirine non-competitively binds
to and inhibits HIV-1 reverse transcriptase. It is best absorbed when taken
with meals and is metabolized by
CYP3A. Rilpivirine does not inhibit or
induce CYP enzymes. Only 1% of a rilpivirine dose is eliminated unchanged
in the urine.
The approval of rilpivirine was
based upon a dose-ranging study
and 3 clinical trials. The dose-ranging
study showed that 25 mg of rilpivirine
daily was shown to be equivalent to
75 mg and 150 mg daily regimens,
and have efficacy comparable to
efavirenz. The efficacy of 25 mg
rilpivirine daily was compared to 600
mg efavirenz daily. Rilpivirine was
found to be non-inferior to efavirenz
in suppressing viral load, based upon
a time-to-loss-of-virological-response
algorithm. However, an increased
risk of virological failure with rilpivirine was observed. The observed
virological failure rate in rilpivirinetreated subjects conferred a higher
rate of overall treatment resistance
and cross-resistance to the NNRTI
class compared to efavirenz. Rilpivirine failures result in etravirine and
efavirenz resistance in most patients
(89%). This is a major disadvantage for
rilpivirine.
The most common adverse effects
observed in clinical trials were nausea
and dizziness. The incidences of rash
and central nervous system adverse
effects with rilpivirine appear to be
less than with efavirenz. Rilpivirine
is classified as pregnancy category B.
Rilpivirine use is contraindicated
when taking inducers of CYP3A or
proton pump inhibitors. Concomitant
administration of these drugs may decrease rilpivirine exposure and increase
the chance for virological failure or
development of resistance. In general,
any substrates, inhibitors, or inducers
of CYP3A have the potential to interact
with rilpivirine.
Rilpivirine was added to the Formulary for continuity of care and to
prevent the development of resistance,
which would be particularly problematic for this agent. It is “non-inferior”
to efavirenz, but is more expensive and
can cause cross-resistance with other
NNRTIs. Rilpivirine could be considered when efavirenz is not tolerated
or when pregnancy is a concern.
Complera® is a combination product
containing emtricitabine [a nucleoside
reverse transcriptase inhibitor or NRTI],
rilpivirine [a non-nucleoside reverse
transcriptase inhibitor or NNRTI],
and tenofovir [a NRTI] with a labeled
indication for the treatment of human
immunodeficiency virus (HIV) infections
in treatment-naïve patients. This
rilpivirine-containing combination
product was also added in the
Formulary.
Rivaroxaban is one of several
new agents receiving attention as
an alternative to warfarin as an oral
anticoagulant. Many of these agents
offer “advantages” over older anticoagulants. However, evidence-based
literature regarding the safety and
efficacy of these new agents needs
further development and careful review
before they establish a more prominent
role in therapy.
Rivaroxaban is the first and only oral
direct factor Xa inhibitor available in the
US. Currently, rivaroxaban has a labeled
indication only for the prevention of
deep vein thrombosis (DVT) in patients
following knee or hip replacement surgery. Randomized controlled data from
4 large ‘RECORD’ trials (Regulation of
Coagulation in Orthopedic Surgery to
Prevent DVT and PE) indicate superiority of rivaroxaban over enoxaparin in
the composite outcome of any DVT, nonfatal PE, or all-cause mortality for the
labeled indication. The trials observed
a similar major bleeding risk in the rivaroxaban treatment arms compared to
enoxaparin; there was a nonsignificant
trend toward increased major bleeding in the rivaroxaban treatment arms.
Being a new agent, rivaroxaban does
not have an extensively documented
safety profile.
Rivaroxaban is available only as a
10-mg tablet. The labeled dosage is
10 mg once daily with or without food
starting 6-8 hours after hip or knee
replacement surgery. It is almost completely bioavailable and exhibits a linear pharmacokinetic profile. Rivaroxaban, unlike some older anticoagulants,
does not require frequent monitoring
or dosage adjustments. Ongoing and
recently published trials are aiming to
expand rivaroxaban’s labeled indications to include stroke prophylaxis in
atrial fibrillation, treatment of symptomatic DVTs, and extended prophylaxis following a symptomatic DVT
event.
Rivaroxaban should be avoided in
patients with renal impairment (CrCl
less than 30 mL/min) and patients with
moderate to severe hepatic impairment. Bleeding is the most common
adverse effect. Increases in hepatic
enzymes have been reported. Rivaroxaban has a boxed warning for epidural
or spinal hematomas in patients receiving epidurals.
Rivaroxaban is competitively priced
for DVT prophylaxis. Similar agents
at Shands include fondaparinux 2.5
mg SC daily (which is 4 times more
expensive), enoxaparin 40 mg SC daily
(which is approximately 3 times more
expensive), enoxaparin 30 mg SC daily
(which is approximately 4 times more
expensive), and heparin 5000 units SC
every 8 hours (which is about 25% less
expensive).
Recently published data showed
efficacy for the use of rivaroxaban for
the off-labeled use for the prevention
of stroke in patients with atrial fibrillation. An FDA advisory committee
recommended that this indication be
added in the labeling; however, final
FDA action is still pending.
Telavancin is a lipoglycopeptide
derivative of vancomycin that received
FDA approval in September 2009 for
the treatment of adult patients with
complicated skin and skin structure infections (cSSSI) caused by susceptible
gram-positive bacteria. In November
2010, Shands at UF added telavancin
in the Formulary.
Telavancin’s spectrum of activity
is similar to vancomycin, with activity against a wide range of aerobic
and anaerobic gram-positive bacteria,
including some multidrug-resistant
strains. Telavancin has a dual mechanism of action: inhibition of peptidoglycan synthesis and disruption
of membrane potential. This dual
mechanism accounts for its enhanced
activity as well as rapid bactericidal
properties.
(continued on next page)
3
ALGORITHM FOR DIAGNOSIS AND MANAGEMENT OF CONGENITAL CMV INFECTION
Diagnosis suspected on basis of clinical illness
1.Obtain CMV IgG and IgM serology
2. Assess IgG avidity (low vs high)
3. Assess for virus in maternal blood and urine via quantitative CMV PRC
Diagnosis of primary maternal infection confirmed
1.Perform amniocentesis at ≥ 15 weeks to assess for virus in amniotic fluid by quantitative PCR or culture.
2. Perform comprehensive ultrasound examination
No virus detected/
normal ultrasound
Virus detected with
normal ultrasound
Virus detected with
abnormal ultrasound
Repeat ultrasound in
2–3 weeks; consider
repeat amniocentesis
Prophylactic Cytogam
at 200 mg/kg
Termination versus
Cytogam at 200 mg/kg
Serial ultrasounds
Reassess findings
Retreat as indicated
No treatment
4
Formulary update, from page 3
Telavancin has been compared
to vancomycin for the treatment of
cSSSI and hospital-acquired pneumonia (HAP) in several non-inferiority
studies. For the treatment of cSSSI,
telavancin was compared to vancomycin in 2 parallel, randomized,
double blind, controlled, phase III
trials (known as the ATLAS trials).
Patients received either telavancin or
vancomycin for 7-14 days. Telavancin
was shown to be non-inferior to vancomycin based on clinical cure rates.
In a subanalysis of the ATLAS trials,
clinical cure rates in the telavancin
treatment group were lower in
patients with impaired renal function
defined as a CrCl less than 50 mL/min,
compared to patients with normal
renal function. The ATTAIN studies
were randomized, double blind, phase
III trials in patients with HAP secondary to suspected or documented
gram-positive pathogens. Once again,
telavancin proved to be non-inferior to
vancomycin for the treatment of HAP.
Telavancin has also been used off-label
for the treatment of bacteremia and
endocarditis.
Rapid infusions can lead to Red-Man
Syndrome; thus, telavancin should be
administered over 60 minutes to reduce
this risk. The most common adverse
events reported are taste disturbance,
nausea, vomiting, and foamy urine.
The drug is classified as pregnancy
category C and carries a black-box
warning about potential fetal risks.
Precaution should also be taken when
prescribing telavancin to patients
with a prolonged baseline QTc interval or taking drugs known to prolong
the QT-interval.
Telavancin was added in the
Formulary and restricted to approval
by the Infectious Diseases or the
Antimicrobial Management Program
for the management of gram-positive
infections in patients who fail or who
are intolerant to other therapies (ie,
vancomycin). Since its inclusion in the
Formulary, telavancin has been used
in only 1 patient. In addition, product
has been discarded due to expiration.
Therefore, telavancin was deleted
from the Formulary and designated
nonformulary and not available due to
low use and high risk of waste.
(continued on other side)
4
Formulary update, from page 4
Brentuximab vedotin is a CD30directed antibody-drug conjugate with
labeled indications for the treatment of
patients with Hodgkin's lymphoma after
failure of autologous stem cell transplant or after failure of at least 2 prior
multi-agent chemotherapy regimens in
patients who are not stem cell transplant candidates and for the treatment
of patients with systemic anaplastic
large cell lymphoma after failure of at
least 1 prior multi-agent chemotherapy
regimen. Brentuximab vedotin was
added in the Chemotherapy Policy.
Cytomegalovirus immune
globulin (CMV IVIG) is an intravenous immune globulin (IgG) with
a standardized amount of antibody
to cytomegalovirus. It has a labeled
indication for the prophylaxis of CMV
disease associated with solid-organ
transplantations. Treatment of CMV
disease is an off-label use.
It is estimated that 5000 to 8000
children per year develop disabilities
(hearing or vision loss, cognitive
impairment) secondary to congenital
CMV infection. During pregnancy, a
small number of pregnancies have
seroepidemiologic evidence of CMV
primary infection and approximately
1% of newborns are infected. Approximately 40% of woman with a
primary infection during pregnancy will
transmit CMV to the fetus. The highest
transmission rates are typically seen in
the third trimester; however, the greatest risk of fetal injury occurs in the first
trimester or early second trimester.
Few treatment options exist for preventing congenital CMV infection or disease. Antiviral therapy and CMV specific
immunoglobulin can be considered to
mitigate complications associated with
primary CMV infection. CMV IVIG has
been shown to suppress CMV replication within the placenta and may prevent
placental dysfunction through reductions
in direct placental damage and improvements in uteroplacental perfusion.
Nigro and colleagues evaluated the
effects of primary CMV infection in 157
pregnant women. A subgroup of 45
women who underwent amniocentesis
and were CMV-positive were offered
CMV IVIG, no immunotherapy, or abortion. Of these 45 women, 31 chose to
receive therapy, 14 declined therapy
(control group), and 10 chose abortion.
CMV IVIG was administered for one
200-mg/kg (maternal weight) dose with
subsequent doses administered pending ultrasound evidence of persistent
infection. Following receipt of CMV
IVIG, 1/31 infants had CMV disease
versus 7/14 in the control group. These
data suggest that CMV IVIG may have
a role in decreasing the incidence
of congenital CMV in babies born
to pregnant women with primary
CMV infection during pregnancy.
In separate analyses, LaTorre and
Nigro identified that CMV IVIG was
associated with significant reduction in placental thickness, placental
inflammation, or placental viral load
in pregnant women with primary
infection.
The P&T Committee endorsed the
use of the treatment of CMV IVIG for
this use based on the algorithm on
page 4. Prior to infusion, the patient
would be premedicated with acetaminophen, diphenhydramine, and
methylprednisolone. Epinephrine will
be available in case of anaphylaxis.
The protocol recommends that Informed Consent be obtained prior to
the use of CMV IVIG administration,
which will highlight the risks and
potential benefits of the product.
Vemurafenib is an oral kinase
inhibitor with a labeled indication
for the treatment of patients with
unresectable or metastatic melanoma
with BFAFV600E mutation as detected
by an FDA-approved test. It is not
recommended for use in patients
with the wild-type BRAF melanoma.
Vemurafenib was added in the Chemotherapy Policy.
ADVERSE DRUG REACTIONS
Bisphosphonates and atypical femur fractures:
A bone of contention
R
5 5
ecently, the FDA released a warning regarding a possible increased
risk of atypical thigh bone fracture in
patients who take bisphosphonates
(BPs).1 The Warnings and Precautions
section of the labeling will be revised
and medication guides will now be
given to inform patients about this
possible risk. Oral and intravenous
BPs approved for osteoporosis will be
affected; changes will not apply to BPs
approved for Paget’s disease, cancer, or
hypercalcemia.
Atypical fractures are so named
because they occur in locations not
typically fractured (subtrochanteric
and/or proximal diaphyseal femur), and
they occur secondary to minimal or no
trauma. Atypical fractures comprise
roughly 8% of osteoporotic fractures.
Femoral fractures, typically grouped
within “other” fracture types in incident analyses, comprised 33% of all
osteoporotic fractures in 2005, 25% of
which were atypical.2,3
The current concern seems contradictory given the drugs’ indication but
consistent with the mechanism of bone
strengthening. BPs inhibit bone turnover to strengthen bones. However,
normal turnover repairs microcracks;
thus, inhibiting this process may lead
to increased bone density without
increased resilience to trauma, leaving
a “more brittle” bone.4
The overarching question is the
strength of association between BP use
and atypical fracture risk. Data from
several observational and randomized
trials suggest a significant increase,
although conclusions are difficult
because of small sample sizes and
methodological limitations.
Before widespread BP use, Salminem and colleagues characterized an
incidence of 1 low-energy fracture
per 10,000 patient-years.2 Observational safety studies later showed a
significantly increased incidence of
atypical fracture with BP use at roughly
2.5/10,000 patient-years.5
Estimates of the association between the use of BPs and atypical
fractures vary widely and are based on
retrospective data. For example, one
case-control study matched atypical
fracture cases to controls with lowenergy fractures in other areas. BP use
was documented in 15/41 (37%) cases
versus 9/82 (11%) controls, producing an odds ratio (OR) of 4.4, (95% CI
1.8-11.4).6 Another study found 19/25
(76%) patients with atypical fracture
were receiving alendronate versus 1/45
(2.2%) without atypical pattern, an OR
of 139 (19-939).7
Though these observational findings
merit consideration, cause and effect
conclusions cannot be made because
of study limitations, which may result
in misclassification bias from unavailability of confirmatory radiographs
and confounding from uncharacterized
comorbidites and medications.
Black and colleagues performed a
secondary analysis of femoral fractures
in 3 large RCTs that assessed efficacy
of BPs.8 The FIT, FLEX, and HORIZON
trials, performed over a maximum 5
years, showed 12 atypical fractures
in 51,000 patient-years. Contrary to
observational findings, relative risk of
atypical fracture with BP treatment
(continued on page 6)
Drugs & Therapy
B
◆
U
◆
L
◆
L
◆
E
◆
T
◆
I
◆
N
Volume 25, No. 9
October 2011
This publication is produced by the
Drug Information and Pharmacy Resource Center under the direction of
the Department of Pharmacy Services
and the Pharmacy and Therapeutics
Committee.
NON-PROFIT ORG.
U.S. POSTAGE
PAID
GAINESVILLE, FL
PERMIT NO. 94
SHANDS
Shands at the University of Florida
DRUG INFORMATION SERVICE
PO Box 100316
Gainesville, FL 32610-0316
EDITOR, DRUGS & THERAPY BULLETIN
Randy C. Hatton, PharmD
DIRECTOR, PHARMACY SERVICES
Alan Knudsen, MS, RPh
CHAIRMAN, PHARMACY &
THERAPEUTICS COMMITTEE
I. David Weiner, MD
Professor of Medicine and Physiology
and Functional Genomics
University of Florida, College of Medicine
EDITING, DESIGN, & PRODUCTION
Shands HealthCare’s Publication Svcs.
© Copyright 2011. All rights reserved.
No portion of the Drugs & Therapy
Bulletin may be reproduced without
the written consent of its editor.
FOR MORE INFORMATION,
VISIT US ONLINE
http://shands.org/professionals/
druginfo/bulletin.asp
Adverse drug reactions, from page 5
versus controls was not statistically
significant.
Grouping these data, however, poses
a problem. Although the number of
patient years is increased, it does not
accurately represent long-term safety.
In other words, although the number
of patient years may be numerically
equivalent, combining data from more
patients from shorter studies is not
equivalent to that of fewer patients
from longer studies.
Another important question is the
effect of therapy duration on risk for
atypical fracture. The study by Lenart and colleagues was remarkable
as it showed statistically greater BP
therapy duration in subtrochanteric
than in intertrochanteric and femoral
neck fractures.6 Although the absolute
numbers of each fracture type were
small (fewer than 10), data over a sixyear period show a trend of increasing
risk for subtrochanteric fracture while
risk decreases for intertrochanteric and
femoral neck fracture. Additionally,
Neviaser showed that among cases
assessable for therapy duration, BP use
was longer at 6.9 years in users with
atypical fractures versus 2.5 years in
those without.7
6
Product-specific effects may be impossible to determine, if not irrelevant
in practice. Although a majority of data
reflects alendronate use, data are heterogeneous and FDA’s recommendation is a class-wide warning for all BPs
indicated for osteoporosis.
FDA may recommend consideration
of a drug holiday or a 5-year limit
to BP therapy. A sustained, but not
increased, benefit has been identified
beyond 3-4 years of therapy. Pooled
analyses of RCT data for decreasing
fracture incidence show similar 5-year
efficacy with continued treatment
compared to 3 years active treatment
followed by placebo.1 Beyond these
5 years, fracture rates are similar,
although strong conclusions are muddied as cohort sizes were nearly halved
at this time point due to different trial
designs.
Few data on drug holidays are available from 14 patients in a study that
stopped risedronate during year 8 then
resumed therapy for 2 subsequent
years.1 Fracture rates post-resumption
were similar to pre-holiday rates,
though the sample size is extremely
small and no data are available to
guide decisions of appropriate population, duration, and timing of holidays.
FDA’s final labeling revision will
likely be conservative. For now, FDA
recommends health care providers be
aware of the possible risk and consider periodic reevaluation of continued therapy beyond 5 years. Patients
should report any thigh or groin pain,
which should be evaluated for possible
femur fracture. Adverse events can be
reported to FDA’s MedWatch Reporting
program at www.fda.gov/MedWatch.
By Ryan Rodriguez, PharmD
REFERENCES
1. Center for Drug Evaluation and Research. Background
Document for Meeting of Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee. September 9, 2011. Available
at http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM270958.pdf.
2. Salminen ST, Pihlajamaki HK, Avikainen VJ, et al. Population based epidemiologic and morphologic study of femoral shaft fractures. Clin Orthop Relat Res 2000;241­9.
3. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence
and Economic Burden of Osteoporosis-Related Fractures
in the United States, 2005–2025. J Bone Miner Res
2007;22:465–475.
4. Ott SM. Editorial: Long-Term Safety of Bisphosphonates.
J Clin Endocr Metab 90(3):1897–1899
5. Nieves JW, Bilezikian JP, Lane JM, et al. Fragility fractures
of the hip and femur: incidence and patient characteristics. Osteoporos Int 2010;21:399­408.
6. Lenart BA, Neviaser AS, Lyman S, et al. Association of
low­energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int
2009;20:1353­62.
7. Neviaser AS, Lane JM, Lenart BA, et al. Low­energy
femoral shaft fractures associated with alendronate use.
J Orthop Trauma 2008;22:346­50.
8. Black DM, Kelly MP, Genant HK, ET AL. Bisphosphonates
and fractures of the subtrochanteric or diaphyseal femur.
N Engl J Med. 2010 May 13;362(19):1761-7